Temporomandibular joint disorders (TMJD) are an important national health problem affecting more than 35 million people in the United States. Mechanical dysfunction of TMJ disc, especially displacement due to tissue degeneration, is central to many TMJ disorders. It is generally believed that pathological mechanical loadings, e.g. sustained jaw clenching or malocclusion, trigger a cascade of molecular events leading to TMJ disc degeneration. However, the mechanism is poorly understood. The normal TMJ disc is a large avascular structure and nutrient supply is crucial for maintaining disc health. The objective of this project is to develop a non-invasive integrated dynamic measuring system (with TMJ imaging, jaw tracking, and TMJ disc finite element model) to establish quantitative relationships between jaw loading (pattern and magnitude), nutrient concentration profiles (oxygen/glucose/lactate), and metabolic rates (oxygen/glucose use and ATP/Lactate production) in TMJ disc. We hypothesize that the nutrient concentrations and cell metabolic rates in TMJ disc are sensitive to the pattern and magnitude of the mechanical loading during jaw function and are therefore potential early bio-indicators for evaluating the impact of mechanical loading on TMJD. Four specific aims will be pursued to test this hypothesis. Aim 1: Determine transport properties of porcine TMJ discs in relation to mechanical strains. Aim 2: Determine porcine TMJ disc cell energy metabolic rates in relation to nutrient concentrations. Aim 3: Develop a non-invasive integrated dynamic measuring system to determine the profiles of nutrient concentrations and cell metabolic rates in TMJ disc. Aim 4: Test the impact of mechanical loading pattern and magnitude on nutrient concentrations and cell metabolic rates in TMJ disc and identify potential bio-indicators based on their mechanical sensitivities. Subject-specific nutrient environment and corresponding cell metabolic rates in TMJ disc during jaw function (Aim 4) will be determined using a mechano-electrochemical signal analyzer (i.e., validated finite element model) with inputs of dynamic TMJ anatomy from Aim 3 as well as tissue transport properties from Aim 1 and cell energy metabolic rates from Aim 2. Successful completion of the proposed aims will 1) establish a new approach to our understanding of TMJ pathology related to joint loading, tissue nutrition, and cell metabolism; 2) identify potential bio-indicators of early TMJ disc degeneration; 3) establish a novel dynamic measuring system to patient-specifically determine those bio-indicators for early diagnosis; 4) provide foundational transport and energy metabolic data for TMJ disc tissue regeneration since nutrition is a key prerequisite for cartilaginous tissue engineering; and 5) demonstrate the feasibility and importance to take this multiscale approach to study joint mechanobiology in general. Although our focus will be on the porcine model, since it is the closest to human TMJ properties, the bio-indicators and measuring systems will all be directly translated to human studies in the future, demonstrating the long term and significant impact of this proposed project in TMJ research.